The present invention relates to novel substituted amides useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to a pharmaceutical method of treatment. More particularly, the novel compounds of the present invention prevent the intestinal absorption of cholesterol in mammals by inhibiting acyl-coenzyme A: cholesterol acyltransferase (ACAT).
The atheromatous plaque, which is the characteristic lesion of atherosclerosis, results from deposition of plasma lipids, mainly cholesteryl esters, in the intima of the arterial wall. Progressive enlargement of the plaque leads to arterial constriction and ultimately coronary heart disease. A number of clinical trials have shown a causal relationship between hypercholesterolemia and coronary heart disease.
Agents that control dietary cholesterol absorption moderate serum cholesterol levels. Dietary cholesterol is absorbed from the intestinal lumen as free cholesterol which must be esterified with fatty acids. This reaction is catalyzed by the enzyme acyl-CoA: cholesterol acyltransferase (ACAT). The resulting cholesteryl esters are packaged into the chylomicrons which are secreted into the lymph. Inhibitors of ACAT not only prevent absorption of dietary cholesterol but also prevent the reabsorption of cholesterol which has been released into the intestine through endogenous regulatory mechanisms, thus lowering serum cholesterol levels and ultimately counteracting the formation or development of atherosclerosis.
British Pat. No. 1,064,252 to Waring, W. S., Published Apr. 5, 1967; U.S. Pat. No. 3,708,514 to Murakami, M., et al., issued Jan. 2, 1973; Kritchevsky, D., et al., Lipids, Vol 12, p. 16-21 (1977); Heider, J. G., et al., Journal of Lipid Research, Vol 24, pp. 1127-1134 (1983); U.S. Pat. No. 4,413,011 to Sircar, I. and Holmes, A., issued Nov. 1, 1983; U.S. Pat. No. 4,465,507 to Konno, K., et al., issued Aug. 14, 1984; Clark, S. B. and Tercyak, A. M., Journal of Lipid Research, Vol. 25, pp. 148-159 (1984); and U.S. Pat. No. 4,554,282 to Sircar, I. and Holmes, A., issued Nov. 19, 1985 describe various substituted amides, some of which are claimed to be used in treating atherosclerosis. However, the aforementioned compounds differ from the ones disclosed in the present invention in that the anilide fragment of the amide does not contain either an imino ether or a cyclic imino ether moiety.